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The human brain is perhaps the most complex object known - it likely has more neurons than the Milky Way has stars. Developmental neurobiology, the study of how the brain comes to be, has been a rich source of biological questions, several of which are illustrated by the articles in this Special Issue. How is the nervous system specified during embryogenesis? How do the vast number of different types of neurons end up in the correct positions with the correct fates? How do growing axons and dendrites find the correct targets and make synapses? And finally, how do neural connections change during life? For some of these questions, we know many of the key molecules; in other cases, we have yet to identify them. Throughout the field, we are just starting to understand how genes work together in networks to achieve the exquisite precision and adaptability of normal development.

Molecular biological and genetic approaches to developmental neurobiology started to bear fruit 2 decades ago and have transformed the field. Since then, our understanding of how a functioning nervous system is created has progressed dramatically. For example, work in Xenopus, chick, and mouse has revealed that neural induction, the process by which the neural ectoderm is specified, is regulated by multiple intersecting signaling pathways, including bone morphogenetic protein and fibroblast growth factor signaling. The first insight into the mechanisms of neural cell fate determination and differentiation came from genetic screens in Drosophila, which provided a paradigm for understanding the function of both positive and negative regulators of neurogenesis, such as the proneural basic helix-loop-helix transcription factors and the Notch inhibitory signaling pathway. More recently, great strides have been made in understanding the properties of multipotent neural stem cells, and it is now appreciated that such multipotent cells exist in the adult and continue to contribute to neurogenesis and regeneration. For axon guidance, attention has focused on four major families of extracellular signals, the Netrins, Slits, Ephrins, and Semaphorins, and their receptors (although there are other signals). The molecular understanding of cell migration, dendrite guidance, and synaptogenesis is much more rudimentary, although some of the signals used for axon guidance play roles here as well. Most of the significant advances in the field have been made in model organisms, but it is now well accepted that basic developmental mechanisms defined in these model systems are remarkably conserved across the animal kingdom.

What do we do next, given the long lists of genes that we have in hand (with more no doubt to come)? Key problems for the future are to understand better what each gene does in vivo and how they work together. New technologies are allowing us to address these problems in new ways. For understanding function, new imaging techniques will be particularly important. Fluorescent proteins now make it routine to label particular neurons, and even particular proteins within those neurons; new modes of microscopy such as multiphoton excitation can visualize these labeled cells or proteins in the context of a living brain. For understanding complex genetic interactions, massively parallel detection techniques will be important. Oligonucleotide microarrays allow us to see how transcriptional profiles are affected by perturbations or developmental changes, whereas their newer cousins, proteome arrays, will allow us to delve into protein interaction networks.

From our present vantage point, we can see important questions looming on the horizon. In addition to conventional genetic mechanisms, there are others whose roles in neural development are just becoming apparent, including epigenetic modifications such as DNA methylation and histone acetylation, as well as microRNAs, which bypass the central dogma of DNA > RNA > protein. There are also systems-level questions that may be hard to address with our standard reductionistic, cell- and molecule-focused approaches. How do the emergent properties of the nervous system develop - can we understand them one cell at a time, or do we need to understand whole circuits? And finally, what can all of our knowledge from model systems start to tell us about human developmental disorders such as epilepsy or autism? One thing we can predict with certainty: the next decade will undoubtedly be just as fast-paced and exciting as the past two.

Chi-Bin Chien and Monica L. Vetter

Special Issue Guest Editors

These articles are provided free online by Wiley-Liss, Inc., the publishers of Developmental Dynamics, and the American Association of Anatomists, as a service to the scientific community.

Page updated November 21, 2005